Use of Continuous Glucose Monitoring and Glucagon-Like Peptide 1 Receptor Agonist Therapy to Achieve Individualized Treatment Goals in Insulin-Treated People With Type 2 Diabetes: A Case Series and Expert Opinion

A 54-year-old man with a 5-year history of type 2 diabetes and hypertension presented to his primary care clinician for uncontrolled diabetes with a recent A1C of 10.3%. He had to take control of his diabetes (A1C <7.0%) before his clinician would perform surgery for a lumbar herniated disc.

His current medications included metformin 1,000 mg twice daily, insulin detemir 52 units every evening, atorvastatin 40 mg daily, and lisinopril 20 mg daily. At the visit, the patient denied significant polyuria or weight loss but reported increased thirst. Glucose data were limited because the patient worked in landscaping and was unable to consistently wash his hands to perform fingerstick blood glucose monitoring checks. His blood pressure was 136/74 mmHg, and his weight was 81.8 kg (BMI 28 kg/m²).

An intermittently scanned continuous glucose monitoring (CGM) system was placed at the initial visit. A 2-week review of the CGM data showed a glucose management indicator (GMI) of 10.1% (mean glucose 284 mg/dL, coefficient of variation [%CV] 29.5%) (Figure 1A). The patient had spent 63% of the time with glucose levels >250 mg/dL, with only 10% time in range (TIR; 70–180 mg/dL) (Figure 1B and C). There was a consistent pattern of fasting hyperglycemia in the range of 180–200 mg/dL, with a >100 mg/dL decline in glucose overnight without hypoglycemia. The CGM report also revealed significant postprandial excursions.

Given that this patient presented with polydipsia and an A1C >10.0% and needed to rapidly improve his glucose control in preparation for surgery, he was referred to a nutritionist, and prandial insulin was added to his treatment regimen. Initial recommendations were to begin a low-carbohydrate diet and add 0.1 units/kg of prandial insulin at each meal to achieve 2-hour postprandial glucose levels <180 mg/dL. Additionally, basal insulin was reduced by 20%, given the significant decline in overnight glucose seen in the CGM data. Finally, he was counseled to further reduce his basal insulin by 10% (4 units) if he observed any overnight or early-morning hypoglycemia. By the time of surgery, he no longer required prandial insulin except with rare high- carbohydrate meals, and he had reduced his basal insulin to 32 units.

One month after surgery, the patient’s CGM report showed significant improvements, including a GMI of 6.9% (Figure 2A) and 73% TIR. Eighteen percent of the time was spent with glucose between 181 and 250 mg/dL, 6% was spent with glucose >250 mg/dL, and 3% was spent with glucose ≤69 mg/dL (Figure 2B–D).

Given the patient’s increasing frequency of hypoglycemia and lack of weight loss despite dietary modification, he was transitioned to an insulin-sparing agent. Thus, the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide was started and titrated from 0.6 to 1.8 mg daily over 4–5 weeks, and basal insulin was further reduced to 20 units.

A 55-year-old man (weight 86.2 kg, BMI 26.7 kg/m²) taking oral agents presented to his primary care clinician with uncontrolled type 2 diabetes. He had a >10-year history of well-controlled diabetes but attributed his worsening glycemic control to a job loss and his wife’s breast cancer diagnosis. His A1C was 13%; thus, basal insulin glargine was initiated with titration to 14 units twice daily. Small change goals for nutrition and activity were also discussed at the visit. His follow-up A1C was 8.3%, and he was referred to endocrinology.

CGM was placed at the initial endocrinology visit. At the second visit, his CGM data showed a TIR of 76% and a GMI of 6.8% (Figure 3A and B). His glycemic variability (%CV) was 36.3%, and he had spent 1% and 4% of the time with glucose <70 and >250 mg/dL, respectively. Additionally, the patient reported some hypoglycemia symptoms at night and before meals, if fasting (Figure 3C and D).

Because of his cardiovascular disease (CVD) risk factors and the occurrence of hypoglycemia, the GLP-1 receptor agonist semaglutide was initiated at 0.25 mg/week, and the glargine was reduced by 20% to 10 units twice daily. Instructions were given to increase semaglutide to 0.5 mg/week and to reduce the glargine to 10 units once daily after 1 month. After 2 months, the semaglutide was increased to 1 mg/week, and the patient was instructed to stop the glargine.

The patient is now taking semaglutide 1 mg/week and two metformin extended-release 750-mg tablets at breakfast. CGM data show a %CV of 26.9% (Figure 4A), and his A1C is 6.8%. The patient is spending no time with glucose <70 mg/dL and only 1% of time with glucose >250 mg/dL (Figure 4B and C). The patient has lost 15 lb, and his BMI has decreased from 26.7 to 24.5 kg/m².

1. How can CGM be used to identify the need for and guide the addition and titration of injectable insulin-sparing agents such as GLP-1 receptor agonists?

2. Compared with basal insulin, how do GLP-1 receptor agonists reduce hypoglycemia risk and improve glycemic control?

3. How should the insulin regimen be adjusted when incorporating GLP-1 receptor agonist therapy?

As illustrated by these cases, A1C measurements do not reflect daily or short-term variations in glucose levels, and glycemic excursions may persist even as A1C improves (1–6). TIR, defined as the percentage of time glucose levels are between 70 and 180 mg/dL, is a marker of glycemic control (7). Although no glycemic metric is perfect, increased TIR has been correlated with decreased risk of microvascular complications, including diabetic retinopathy, nephropathy, and peripheral neuropathy (8–14). A large prospective study also showed that the percentage of TIR is correlated with macrovascular complications, including CVD-related and all-cause mortality (15).

CGM data can provide a more comprehensive assessment of glycemic control, including TIR, time above range, time below range, and glycemic variability (%CV); for this reason, CGM is an important tool that can highlight hypoglycemia risk and discover underlying nocturnal hypoglycemia (5,11,16–20). A high %CV is a marker of hypoglycemia risk, and an ideal %CV is <36%, with some studies suggesting that individuals taking insulin or sulfonylureas would benefit from targeting a %CV <33% (5,21–24). CGM also increases convenience for patients by avoiding a requirement for fingersticks, enables patients and providers to observe glucose trends in real time, and enables the setting of individualized alarms for predicted low and high glucose levels (5). Importantly, CGM can support individualized escalation or de-escalation of treatment in the short term, without needing to wait for the next A1C measurement (5). CGM has been recommended for patients with type 2 diabetes who are not achieving glycemic targets and/or those who are experiencing challenging hypoglycemic episodes (5).

In the first case presented here, CGM data revealed hypoglycemia risk, as demonstrated by the overnight decline in glucose levels even in the setting of original hyperglycemia (as indicated by both high A1C and CGM data). Despite CGM being active only 65% of the time, these data aided in the decision to reduce basal insulin, which may not have been considered in the context of A1C only. Notably, titration of basal insulin based on fasting glucose alone may lead to overbasalization, especially for patients starting with evening postprandial hyperglycemia. Thus, CGM is an important tool to help properly titrate insulin (25). Table 1 provides general guidelines on CGM use in the context of insulin therapy.

In the second case presented here, A1C had improved significantly, and the GMI revealed a recent improvement in glycemic control (6.8%). However, a more detailed review of the CGM data revealed instances of hypoglycemia and glycemic variability (%CV 36.2%), indicating that treatment was not yet optimized.

The use of personal CGM systems (owned by the user) is becoming increasingly more common as Medicare coverage has expanded beyond those on intensive insulin therapy to include those on basal insulin only and those not on insulin therapy who have significant hypoglycemia. However, professional CGM (owned by the clinic and intended for short-term use by patients) is still an important tool for those who cannot afford personal CGM, are not interested in ongoing CGM use, or are not on insulin therapy and do not have known hypoglycemia. Professional CGM use may be most appropriate when supporting lifestyle modifications or when medication changes are initiated.

To successfully incorporate CGM into clinical practice, designated clinic personnel should be responsible for training patients on sensor insertion and use and for ensuring that data are accessible in the clinic. These designated personnel should receive appropriate training and may include medical assistants, registered nurses, and diabetes care and education specialists.

Finally, to ensure that patients obtain the maximum benefit from CGM use, clinics should institute a proper billing workflow for sensor insertion and interpretation of real-time CGM data. When interpreting these data, it should be noted that individual goals are based on patient characteristics and risk profiles. For example, older adults may have less strict glycemic targets, and tighter targets may be more appropriate during pregnancy (24). Helpful resources for clinicians initiating CGM include the CGM Professional and Personal Playbooks from the Association of Diabetes Care & Education Specialists (26) and a 2019 guide to CGM data review and interpretation by Aleppo and Webb (27).

In the cases presented here, CGM data also highlight the improved glycemic control and reduced hypoglycemia and glycemic variability that can be achieved by incorporating a GLP-1 receptor agonist in the diabetes care plan (28). These cases are models of how to individualize therapy and leverage the benefits of GLP-1 receptor agonist therapy to support patient-centered goals. The American Diabetes Association (ADA) Standards of Care in Diabetes (29) and international ADA-European Association for the Study of Diabetes consensus guidelines (30) recommend using a GLP-1 receptor agonist as an initial injectable and/or replacing insulin with an insulin-sparing injectable. Current ADA recommendations and statements from the American College of Cardiology and other organizations also support GLP-1 receptor agonist therapy for patients with type 2 diabetes with established CVD or high risk for CVD or when weight loss is also a goal of treatment (29,31–33).

Overall, GLP-1 receptor agonists are associated with improved glycemic control, decreased hypoglycemia, weight loss, improved lipid profiles, lower blood pressure, and decreased CVD risk (34–48). These agents also modestly improve diabetes-related renal outcomes, although the underlying mechanisms remain unclear (32,49–52). The most common adverse events associated with GLP-1 receptor agonists are gastrointestinal events (e.g., nausea, vomiting, and diarrhea) (32,49).

GLP-1 receptor agonists come in many forms, including short-acting, with a half-life of 2–4 hours (e.g., exenatide and lixisenatide); long-acting, with a half-life of >12 hours (e.g., dulaglutide, liraglutide, semaglutide, and exenatide extended release); and dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists (e.g., tirzepatide) (53–55). Because GLP-1 receptor agonists have a glucose-dependent mechanism of action, they are associated with low hypoglycemia risk (54,56).

Despite the clear benefits of GLP-1 receptor agonists and guidelines supporting their use in patients with or at risk for CVD and those not at optimal glycemic control (29,31–33), there is a paucity of practical literature demonstrating how to add these agents, especially in the setting of insulin use. When initiating a GLP-1 receptor agonist, it is important to assess both the current total dose of insulin in the context of weight and current glycemic control (by A1C or CGM data, if available). Based on this assessment, a GLP-1 receptor agonist may be initiated with no reduction (if A1C is ≥8.0–8.5%) or a 20% reduction (if A1C is <8.0–8.5%) in insulin dose (Figure 5 and Table 2). It is important to note that modifying insulin doses is an individualized process and should be implemented with consideration of both the patient’s prescribed and reported actual total daily insulin dose. Once the GLP-1 receptor agonist dose is maximized, further adjustments to the insulin dose and/or the addition of other agents for cardiovascular or renal indications may be considered, if necessary. Additionally, because GLP-1 receptor agonists are associated with weight loss, dosages of concomitant medications may need to be adjusted accordingly.

When initiating a GLP-1 receptor agonist, clinicians should discuss its efficacy, potential benefits (including reduced risk of hypoglycemia and cardiovascular protection), and side effects with the patient. CGM can then reinforce this discussion by providing immediate feedback about improved glycemic control.

• CGM should be considered as a tool to use when individualizing and optimizing insulin therapy.

• GLP-1 receptor agonists improve glycemic efficacy in people treated with insulin, allowing for reductions in the insulin dose and addressing multiple aspects of hyperglycemia throughout the day.

• The combination of diagnostic CGM with GLP-1 receptor agonist therapy in patients with type 2 diabetes who are on insulin therapy can identify and correct therapeutic gaps.

The authors thank Adele Musicant, PhD, of PRECISIONscientia in Yardley, PA, for her assistance with reference gathering, draft development, and editorial support. The authors also thank Cory Gamble, DO, FACE, of Novo Nordisk, for providing a medical accuracy review. This assistance was supported by Novo Nordisk.

N.M.E. has received educational grants from Merck and Novo Nordisk, served on advisory boards for Dexcom and Novo Nordisk, and received investigator-initiated grants from Dexcom. V.R.A. has served as a consultant for Applied Therapeutics, Fractyl, Novo Nordisk, Pfizer, and Sanofi; received institutional contracts for research from Applied Therapeutics/Medpace, Eli Lilly, Novo Nordisk, Premier/Fractyl, and Sanofi; and reports spousal employment at Janssen. R.J.G. is supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award numbers P30DK111024-04S2 and 1K23DK123384-03; has received unrestricted research support to Emory University from Dexcom, Eli Lilly, and Novo Nordisk; and has received consulting/honoraria fees from Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Sanofi, and Weight Watchers. A.L.P. has served as a consultant for Abbott, Blue Circle Health, Medscape, and Vertex; received research grants from Abbott and Insulet; and holds stock options with Omada Health and Teladoc. J.H.S. has served as a consultant for Abbott, Bayer, and Novo Nordisk and served on advisory boards for Abbott, AstraZeneca, Bayer, Eli Lilly, Nevro, and Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.

N.M.E. and J.H.S. provided the cases discussed in this article. All of the authors contributed to writing, revising, and editing the manuscript and approved the final version for submission. N.M.E. is the guarantor of this work and, as such, had full access to all the data in the case studies and takes responsibility for the integrity of the data and the accuracy of the content.